Skip to main content
Log in

Removal of antineoplastic drugs cyclophosphamide, ifosfamide, and 5-fluorouracil and a vasodilator drug pentoxifylline from wastewaters by ozonation

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

We investigated the ozonation of the antineoplastic drugs cyclophosphamide (CP), ifosfamide (IF), and 5-fluorouracil (5-FU) and of the vasodilator pentoxifylline (PEN) in distilled water, in pharmaceutical wastewater, and in hospital effluent at pH 5–11. Under an alkaline pH of 11, all of the target compounds rapidly degraded through the attack of hydroxyl radicals, which resulted in their complete removal within 5 min at an ozone supply rate of 3 g O3/h. Under acidic pH conditions, such as pH 5.6, CP and IF exhibited slower removal rates; however, compounds with unsaturated C-C bonds, such as 5-FU and PEN, were still removed at rapid rates under acidic conditions. Although the parent compounds were removed within minutes, the resulting ozonation byproducts were resistant to further ozonation and possessed increased Microtox acute toxicity. In distilled water, the resulting ozonation products exhibited minimal mineralization but high acute toxicity, whereas in naturally buffered pharmaceutical and hospital effluents, the byproducts were more amenable to removal and detoxification.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Adams CD, Cozzens RA, Kim BJ (1997) Effects of ozonation on the biodegradability of substituted phenols. Water Res 31:2655–2663

    Article  CAS  Google Scholar 

  • Andreozzi R, Canterino M, Marotta R, Paxeus N (2005) Antibiotic removal from wastewaters: the ozonation of amoxicillin. J Hazard Mater 122:243–250

    Article  CAS  Google Scholar 

  • Andreozzi R, Canterino M, Giudice RL, Marotta R, Pinto G, Pollio A (2006) Lincomycin solar photodegradation, algal toxicity and removal from wastewaters by means of ozonation. Water Res 40:630–638

    Article  CAS  Google Scholar 

  • Boluda R, Quintanilla JF, Bonilla JA, Sáez E, Gamón M (2002) Application of the Microtox® test and pollution indices to the study of water toxicity in the Albufera Natural Park (Valencia, Spain). Chemosphere 46:355–369

    Article  CAS  Google Scholar 

  • Brooke S, Newcombe G, Nicholson B, Klass G (2006) Decrease in toxicity of microcystins LA and LR in drinking water by ozonation. Toxicon 48:1054–1059

    Article  CAS  Google Scholar 

  • Buerge IJ, Buser H-R, Poiger T, Müller MD (2006) Occurrence and fate of the cytostatic drugs cyclophosphamide and Ifosfamide in wastewater and surface waters. Environ Sci Technol 40:7242–7250

    Article  CAS  Google Scholar 

  • Clara M, Strenn B, Gans O, Martinez E, Kreuzinger N, Kroiss H (2005) Removal of selected pharmaceuticals, fragrances and endocrine disrupting compounds in a membrane bioreactor and conventional wastewater treatment plants. Water Res 39:4797–4807

    Article  CAS  Google Scholar 

  • Dantas RF, Canterino M, Marotta R, Sans C, Esplugas S, Andreozzi R (2007) Bezafibrate removal by means of ozonation: primary intermediates, kinetics, and toxicity assessment. Water Res 41:2525–2532

    Article  CAS  Google Scholar 

  • David Yao CC, Haag WR (1991) Rate constants for direct reactions of ozone with several drinking water contaminants. Water Res 25:761–773

    Article  Google Scholar 

  • Dewhurst RE, Wheeler JR, Chummun KS, Mather JD, Callaghan A, Crane M (2002) The comparison of rapid bioassays for the assessment of urban groundwater quality. Chemosphere 47:547–554

    Article  CAS  Google Scholar 

  • Dowideit P, von Sonntag C (1998) Reaction of ozone with ethene and its methyl- and chlorine-substituted derivatives in aqueous solution. Environ Sci Technol 32:1112–1119

    Article  CAS  Google Scholar 

  • Garcia-Ac A, Broséus R, Vincent S, Barbeau B, Prévost M, Sauvé S (2010) Oxidation kinetics of cyclophosphamide and methotrexate by ozone in drinking water. Chemosphere 79:1056–1063

    Article  CAS  Google Scholar 

  • Haag WR, Yao CCD (1992) Rate constants for reaction of hydroxyl radicals with several drinking water contaminants. Environ Sci Technol 26:1005–1013

    Article  CAS  Google Scholar 

  • Hao OJ, Shin C-J, Lin C-F, Jeng F-T, Chen Z-C (1996) Use of microtox tests for screening industrial wastewater toxicity. Water Sci Technol 34:43–50

    Article  CAS  Google Scholar 

  • Hengstler JG, Fuchs J, Oesch F (1992) DNA strand breaks and DNA cross-links in peripheral mononuclear blood cells of ovarian cancer patients during chemotherapy with cyclophosphamide/carboplatin. Cancer Res 52:5622–5626

    CAS  Google Scholar 

  • Hoigné J, Bader H (1976) The role of hydroxyl radical reactions in ozonation processes in aqueous solutions. Water Res 10:377–386

    Article  Google Scholar 

  • Hoigne J, Bader H (1979) Ozonation of water: selectivity and rate of oxidation of solutes. Ozone Sci Eng 1:73–85

    Article  CAS  Google Scholar 

  • Hua WY, Bennett ER, Maio X-S, Metcalfe CD, Letcher RJ (2006) Seasonality effects on pharmaceuticals and s-triazine herbicides in wastewater effluent and surface water from the Canadian side of the upper Detroit River. Environ Toxicol Chem 25:2356–2365

    Article  CAS  Google Scholar 

  • Inaba M, Mitsuhashi J, Sawada H, Miike N, Naoe Y, Daimon A, Koizumi K, Tsujimoto H, Fukushima M (1996) Reduced activity of anabolizing enzymes in 5-fluorouracil-resistant human stomach cancer cells. Cancer Sci 87:212–220

    Article  CAS  Google Scholar 

  • Indrayanto G, Syahrani A, Moegihardjo, Soeharyono, Lianawati T, Wahyuningsih I, Aditama L, Brittain HG (1998) Pentoxifylline. In: Harry GB (Editor), Analytical profiles of drug substances and excipients. Academic, pp. 295-339

  • Johnstone EC, Lind MJ, Griffin MJ, Boddy AV (2000) Ifosfamide metabolism and DNA damage in tumour and peripheral blood lymphocytes of breast cancer patients. Cancer Chemother Pharm 46:433–441

    Article  CAS  Google Scholar 

  • Kaiser K (1998) Correlations of Vibrio fischeri bacteria test data with bioassay data for other organisms. Environ Health Perspect 106:583

    Article  CAS  Google Scholar 

  • Kang C-S (2012) Photodegradation of pentoxifylline in aquatic environments. Graduate Institute of Environment Engineering, National Taiwan University Master Thesis

  • Kim SD, Cho J, Kim IS, Vanderford BJ, Snyder SA (2007) Occurrence and removal of pharmaceuticals and endocrine disruptors in South Korean surface, drinking, and waste waters. Water Res 41:1013–1021

    Article  CAS  Google Scholar 

  • Krasner SW, Weinberg HS, Richardson SD, Pastor SJ, Chinn R, Sclimenti MJ, Onstad GD, Thruston AD (2006) Occurrence of a new generation of disinfection byproducts. Environ Sci Technol 40:7175–7185

    Article  CAS  Google Scholar 

  • Kümmerer K, Steger-Hartmann T, Meyer M (1997) Biodegradability of the anti-tumour agent ifosfamide and its occurrence in hospital effluents and communal sewage. Water Res 31:2705–2710

    Article  Google Scholar 

  • Leonhardt H, Grigoleit H-G (1977) Effects of pentoxifylline on red blood cell deformability and blood viscosity under hyperosmolar conditions. Naunyn-Schmiedeberg’s Arch Pharmacol 299:197–200

    Article  CAS  Google Scholar 

  • Li K, Yediler A, Yang M, Schulte-Hostede S, Wong MH (2008) Ozonation of oxytetracycline and toxicological assessment of its oxidation by-products. Chemosphere 72:473–478

    Article  CAS  Google Scholar 

  • Lin AY-C, Yu T-H, Lin C-F (2008) Pharmaceutical contamination in residential, industrial, and agricultural waste streams: risk to aqueous environments in Taiwan. Chemosphere 74:131–141

    Article  CAS  Google Scholar 

  • Mahnik SN, Rizovski B, Fuerhacker M, Mader RM (2004) Determination of 5-fluorouracil in hospital effluents. Anal Bioanal Chem 380:31–35

    CAS  Google Scholar 

  • Mahnik SN, Lenz K, Weissenbacher N, Mader R, Fuerhacker M (2007) Fate of 5-fluorouracil, doxorubicin, epirubicin, and daunorubicin in hospital wastewater and their elimination by activated sludge and treatment in a membrane-bio-reactor system. Chemosphere 66:30–37

    Article  CAS  Google Scholar 

  • Martin N, Benezet-Toulze M, Laplace C, Faivre M, Langlais B (1992) Design and efficiency of ozone contactors for disinfection. Ozone Sci Eng 14:391–405

    Article  CAS  Google Scholar 

  • McDowell DC, Huber MM, Wagner M, von Gunten U, Ternes TA (2005) Ozonation of carbamazepine in drinking water: identification and kinetic study of major oxidation products. Environ Sci Technol 39:8014–8022

    Article  CAS  Google Scholar 

  • Metcalfe CD, Koenig BG, Bennie DT, Servos M, Ternes TA, Hirsch R (2003) Occurrence of neutral and acidic drugs in the effluents of Canadian sewage treatment plants. Environ Toxicol Chem 22:2872–2880

    Article  CAS  Google Scholar 

  • Moldovan Z (2006) Occurrences of pharmaceutical and personal care products as micropollutants in rivers from Romania. Chemosphere 64:1808–1817

    Article  CAS  Google Scholar 

  • Mone MK, Chandrasekhar KB (2010) Degradation studies of pentoxifylline: isolation and characterization of a novel gem-dihydroperoxide derivative as major oxidative degradation product. J Pharm Biomed Anal 53:335–342

    Article  CAS  Google Scholar 

  • Mullot J-U, Karolak S, Fontova A, Huart B, Levi Y (2009) Development and validation of a sensitive and selective method using GC/MS-MS for quantification of 5-fluorouracil in hospital wastewater. Anal Bioanal Chem 394:2203–2212

    Article  CAS  Google Scholar 

  • Phyu YL, Warne MSJ, Lim RP (2005) Effect of river water, sediment and time on the toxicity and bioavailability of molinate to the marine bacterium Vibrio fischeri (Microtox). Water Res 39:2738–2746

    Article  CAS  Google Scholar 

  • Ribo JM, Kaiser KLE (1983) Effects of selected chemicals to photoluminescent bacteria and their correlations with acute and sublethal effects on other organisms. Chemosphere 12:1421–1442

    Article  CAS  Google Scholar 

  • Richardson SD, Thruston AD, Caughran TV, Chen PH, Collette TW, Floyd TL, Schenck KM, Lykins BW, G-r S, Majetich G (1999) Identification of new ozone disinfection byproducts in drinking water. Environ Sci Technol 33:3368–3377

    Article  CAS  Google Scholar 

  • Ringwood AH, DeLorenzo ME, Ross PE, Holland AF (1997) Interpretation of Microtox® solid-phase toxicity tests: the effects of sediment composition. Environ Toxicol Chem 16:1135–1140

    Article  CAS  Google Scholar 

  • Rowney NC, Johnson AC, Williams RJ (2009) Cytotoxic drugs in drinking water: a prediction and risk assessment exercise for the thames catchment in the United Kingdom. Environ Toxicol Chem 28:2733–2743

    Article  CAS  Google Scholar 

  • Sacher F, Ehmann M, Gabriel S, Graf C, Brauch H-J (2008) Pharmaceutical residues in the river Rhine—results of a one-decade monitoring programme. J Environ Monit 10:664–670

    Article  CAS  Google Scholar 

  • Scott AC, Zubot W, MacKinnon MD, Smith DW, Fedorak PM (2008) Ozonation of oil sands process water removes naphthenic acids and toxicity. Chemosphere 71:156–160

    Article  CAS  Google Scholar 

  • Snyder SA, Wert EC, Rexing DJ, Zegers RE, Drury DD (2006) Ozone oxidation of endocrine disruptors and pharmaceuticals in surface water and wastewater. Ozone Sci Eng 28:445–460

    Article  CAS  Google Scholar 

  • Staehelin J, Hoigne J (1982) Decomposition of ozone in water: rate of initiation by hydroxide ions and hydrogen peroxide. Environ Sci Technol 16:676–681

    Article  CAS  Google Scholar 

  • Steger-Hartmann T, Kümmerer K, Schecker J (1996) Trace analysis of the antineoplastics ifosfamide and cyclophosphamide in sewage water by twostep solid-phase extraction and gas chromatography-mass spectrometry. J Chromatogr A 726:179–184

    Article  CAS  Google Scholar 

  • Tanaka K, Abe K, Sheng CY, Hisanaga T (1992) Photocatalytic wastewater treatment combined with ozone pretreatment. Environ Sci Technol 26:2534–2536

    Article  CAS  Google Scholar 

  • Ternes TA (1998) Occurrence of drugs in German sewage treatment plants and rivers. Water Res 32:3245–3260

    Article  CAS  Google Scholar 

  • Trapido M, Veressinina J, Munter R (1994) Ozonation and AOP treatment of phenanthrene in aqueous solutions. Ozone Sci Eng 16:475–485

    Article  CAS  Google Scholar 

  • von Gunten U (2003) Ozonation of drinking water: part I. Oxidation kinetics and product formation. Water Res 37:1443–1467

    Article  Google Scholar 

  • Wang C, Yediler A, Lienert D, Wang Z, Kettrup A (2003) Ozonation of an azo dye C.I. Remazol Black 5 and toxicological assessment of its oxidation products. Chemosphere 52:1225–1232

    Article  CAS  Google Scholar 

  • Wolska L, Sagajdakow A, Kuczyńska A, Namieśnik J (2007) Application of ecotoxicological studies in integrated environmental monitoring: possibilities and problems. TrAC Trends Anal Chem 26:332–344

    Article  CAS  Google Scholar 

  • Yin J, Shao B, Zhang J, Li K (2010) A preliminary study on the occurrence of cytostatic drugs in hospital effluents in Beijing, China. Bull Environ Contam Toxicol 84:39–45

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Angela Yu-Chen Lin.

Additional information

Responsible editor: Leif Kronberg

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 17 kb)

ESM 2

(DOCX 17 kb)

ESM 3

(DOCX 17 kb)

ESM 4

(DOCX 17 kb)

ESM 5

(DOCX 66 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, A.YC., Hsueh, J.HF. & Hong, P.K.A. Removal of antineoplastic drugs cyclophosphamide, ifosfamide, and 5-fluorouracil and a vasodilator drug pentoxifylline from wastewaters by ozonation. Environ Sci Pollut Res 22, 508–515 (2015). https://doi.org/10.1007/s11356-014-3288-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-014-3288-7

Keywords

Navigation